Jayesh A. Kulkarni
University of British Columbia
GeneMessenger RNAProdrugGene silencingBiophysicsVesicleNanoparticleSmall moleculeCationic polymerizationLiposomeChemistryCytoplasmBilayerIn vivoSmall interfering RNANucleic acidSystemic administrationPhosphatidylcholineBiodistributionCholesterolPhospholipidDrug deliveryDrugRNAComputational biologyMedicineCell biologyPharmacology
31Publications
14H-index
709Citations
Publications 32
Newest
#1Jayesh A. Kulkarni (UBC: University of British Columbia)H-Index: 14
#2Dominik Witzigmann (UBC: University of British Columbia)H-Index: 16
Last. Roy van der Meel (TU/e: Eindhoven University of Technology)H-Index: 21
view all 7 authors...
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#1Anthony Tam (UBC: University of British Columbia)H-Index: 11
#2Pascal Leclair (UBC: University of British Columbia)H-Index: 6
Last. Gurpreet K. Singhera (UBC: University of British Columbia)H-Index: 16
view all 14 authors...
Genome-wide association studies have shown that a gene variant in the Family with Sequence Similarity 13, Member A (FAM13A) is strongly associated with reduced lung function and the appearance of respiratory symptoms in patients with Chronic Obstructive Pulmonary Disease (COPD). A key player in smoking-induced tissue injury and airway remodeling is the transforming growth factor β1 (TGFβ1). To determine the role of FAM13A in TGFβ1 signaling, FAM13A-/- airway epithelial cells were generated using...
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#1Jayesh A. Kulkarni (UBC: University of British Columbia)H-Index: 14
#2Sam ChenH-Index: 16
Last. Yuen Yi C. Tam (UBC: University of British Columbia)H-Index: 23
view all 3 authors...
Lipid-based formulations have been developed to improve stability profiles, tolerability, and toxicity profiles of small molecule drugs. However, manufacture of such formulations involving lipophilic compounds can be labor-intensive and difficult to scale because of solubility and solvent compatibility issues. We have developed a rapid and scalable approach using rapid-mixing techniques to generate homogeneous lipid nanoparticle (LNP) formulations of siRNA, triglycerides, and hydrophilic weak-ba...
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#1Jayesh A. Kulkarni (UBC: University of British Columbia)H-Index: 14
#2Dominik WitzigmannH-Index: 16
Last. Roy van der Meel (TU/e: Eindhoven University of Technology)H-Index: 21
view all 7 authors...
The increasing number of approved nucleic acid therapeutics demonstrates the potential to treat diseases by targeting their genetic blueprints in vivo. Conventional treatments generally induce therapeutic effects that are transient because they target proteins rather than underlying causes. In contrast, nucleic acid therapeutics can achieve long-lasting or even curative effects via gene inhibition, addition, replacement or editing. Their clinical translation, however, depends on delivery technol...
1 CitationsSource
#1Linde Schoenmaker (LEI: Leiden University)H-Index: 1
#2Dominik Witzigmann (UBC: University of British Columbia)H-Index: 16
Last. Daan J.A. Crommelin (UU: Utrecht University)H-Index: 90
view all 7 authors...
Abstract A drawback of the current mRNA-lipid nanoparticle (LNP) COVID-19 vaccines is that they have to be stored at (ultra)low temperatures. Understanding the root cause of the instability of these vaccines may help to rationally improve mRNA-LNP product stability and thereby ease the temperature conditions for storage. In this review we discuss proposed structures of mRNA-LNPs, factors that impact mRNA-LNP stability and strategies to optimize mRNA-LNP product stability. Analysis of mRNA-LNP st...
14 CitationsSource
#1Julian Vogler (UBC: University of British Columbia)H-Index: 1
#2Roland Böttger (UBC: University of British Columbia)H-Index: 3
Last. Shyh-Dar Li (UBC: University of British Columbia)H-Index: 32
view all 18 authors...
We demonstrated that phospholipid-free small unilamellar vesicles (PFSUVs) composed of TWEEN 80 and cholesterol (25/75, mol%) could be fabricated using a staggered herringbone micromixer with precise controlling of their mean size between 54 nm and 147 nm. Increasing the temperature or decreasing the flow rate led to an increase in the resulting particle diameter. In zebrafish embryos, 120-nm PFSUVs showed 3-fold higher macrophage clearance compared to the 60-nm particles, which exhibited prolon...
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#1Amy Henrickson (U of L: University of Lethbridge)H-Index: 4
#2Jayesh A. KulkarniH-Index: 14
Last. Borries Demeler (UM: University of Montana)H-Index: 57
view all 6 authors...
Previous work suggested that lipid nanoparticle (LNP) formulations, encapsulating nucleic acids, display electron-dense morphology when examined by cryogenic-transmission electron microscopy (cryo-TEM). Critically, the employed cryo-TEM method cannot differentiate between loaded and empty LNP formulations. Clinically relevant formulations contain high lipid-to-nucleic acid ratios (10-25 (w/w)), and for systems that contain mRNA or DNA, it is anticipated that a substantial fraction of the LNP pop...
3 CitationsSource
#1Takeshi Terada (UBC: University of British Columbia)H-Index: 1
#1Takeshi Terada (UBC: University of British Columbia)H-Index: 1
Last. Pieter R. Cullis (UBC: University of British Columbia)H-Index: 117
view all 7 authors...
Lipid nanoparticles (LNPs) containing short-interfering RNA (LNP-siRNA systems) are a promising approach for silencing disease-causing genes in hepatocytes following intravenous administration. LNP-siRNA systems are generated by rapid mixing of lipids in ethanol with siRNA in aqueous buffer (pH 4.0) where the ionizable lipid is positively charged, followed by dialysis to remove ethanol and to raise the pH to 7.4. Ionizable cationic lipids are the critical excipient in LNP systems as they drive e...
3 CitationsSource
#1Takeshi Terada (Mitsubishi Tanabe Pharma)
#1Takeshi Terada (Mitsubishi Tanabe Pharma)H-Index: 1
Last. Pieter R. Cullis (UBC: University of British Columbia)H-Index: 117
view all 5 authors...
Liposomes containing ionizable cationic lipids have been widely used for the delivery of nucleic acids such as small-interfering RNA and mRNA. The utility of cationic lipids with a permanent positive charge, however, is limited to in vitro transfection of cultured cells due to its dose-limiting toxic side effects observed in animals. Several reports have suggested that the permanently charged cationic lipids induce reactive oxygen species (ROS) and ROS-mediated toxicity in cells. We therefore hy...
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#1Jayesh A. KulkarniH-Index: 14
#2Sarah B. ThomsonH-Index: 2
Last. Blair R. LeavittH-Index: 80
view all 10 authors...
Lipid nanoparticle (LNP) formulations of nucleic acid are leading vaccine candidates for COVID-19, and enabled the first approved RNAi therapeutic, Onpattro. LNPs are composed of ionizable cationic lipids, phosphatidylcholine, cholesterol, and polyethylene glycol (PEG)-lipids, and are produced using rapid-mixing techniques. These procedures involve dissolution of the lipid components in an organic phase and the nucleic acid in an acidic aqueous buffer (pH 4). These solutions are then combined us...
7 CitationsSource